Contrast-related allergy

I. What every physician needs to know.

Iodinated contrast media is generally safe. The reaction is due to the hypertonicity of the media, not the iodine. High osmolality contrast agents have a higher risk of reaction. Lower osmolality contrast agents (especially non-ionic) tend to be better tolerated and have lower incidence of reactions, but they are more costly (up to 10 times more) which limits their exclusive use. Examples of low contrast ionic agents include Magnevist®, Omniscan®, and Optimark®; low contrast non-ionic agents include Omnipaque®, Optiray®, Isovue®, and Ultravist®. Examples of high osmolality contrast ionic agents include Renografin®, Hypaque®, and Conray®.

Adverse reactions tend to mild, self-limited, and idiosyncratic (not related to dose or prior exposure). Severe or immediate reactions tend to be anaphylactoid, rather than anaphylactic, and are due to non-IgE (non-immunoglobulin E) mediated activation of mast cells and basophils. Thus sensitization does not occur since it is non-immune mediated.

Those with prior reactions to contrast, asthma, or hay fever will have a higher incidence of reactions than the general population.

Symptoms tend to occur around 30 minutes after exposure to the contrast agent.

A. History Part I: Pattern Recognition:

Initial symptoms may be mild, like hives or itching. More moderate reactions can include nausea, vomiting, chills, abdominal cramps, facial or laryngeal edema, shortness of breath, wheezing, hypertension, and headache. Severe reactions include bronchoconstriction, convulsions, pulmonary edema, arrhythmia, shock, or cardiopulmonary arrest. Non-idiosyncratic reactions include metallic taste in mouth, vasovagal response, and sensation of warmth; these tend to be dose dependent.

Delayed reactions can occur 1 hour to 7 days after exposure, are often mild, and include flu-like symptoms, nausea, diarrhea, rash, pruritus, urticaria, abdominal pain, and dizziness; these tend to occur more with ionic contrast agents.

Extravasation reactions cause tissue damage like skin blistering due to contrast toxicity and can increase the risk of compartment syndrome. If enteric contrast (barium) extravasates, it can lead to extensive fibrosis. Thus if a patient is at risk for intra-abdominal extravasation (concern for tube misplacement, perforation, sinus tract/fistula), use a water soluble contrast (like Gastrografin®).

In 2010, the US Food and Drug Administration (FDA) released warnings about the association between nephrogenic systemic fibrosis (NSF) and gadolinium based contrast agents in patients with kidney disease. The FDA review lists Magnevist®, Omniscan®, and Optimark® as having a higher risk of NSF than other contrast agents.

Separately, contrast-induced nephropathy is a multifactorial event (pre-existing renal hemodynamic changes plus contrast-induced vasoconstriction and direct cellular toxicity) that results in absolute increase of creatinine by 0.5 milligram/deciliter (mg/dL) or 25% elevation in baseline creatinine occurring 1-3 days after contrast exposure. Given its complex nature and resultant acute, oliguric renal failure, it will not be discussed here since it is not a contrast "allergy" per se.

B. History Part 2: Prevalence:

Prevalence is 4-8% overall, with anaphylaxis occurring in 1% and death occurring in less than 0.00001%. The rates of all reactions tend to be higher for high osmolarity contrast media (5-12%) and less for low osmolarity contrast media (0.2-0.7%, for all reactions, and 0.04%, for serious reactions), which are the more commonly used agents today.

C. History Part 3: Competing diagnoses that can mimic contrast-related allergy

Asthma exacerbation or other acute dermatoses (allergic or contact dermatitis, viral exanthem) may be the most common diagnoses that could mimic illness but these should be noted or seen prior to contrast exposure. Also, anaphylactic reactions may produce similar symptoms as anaphylactoid type reactions.

D. Physical Examination Findings.

Most reactions are mild and self-limited, thus no major examination findings. For moderate-to-severe reactions, findings may include hives, wheezing, respiratory distress or hypoxia, hypotension, tachycardia (adrenaline response) or bradycardia (vagal mediated), decreased level of consciousness, or convulsions.

E. What diagnostic tests should be performed?

None

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

None

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

None

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Often patients will need no further diagnostic testing if clinical judgment deems this to be only a contrast-related allergy. Thus any detailed diagnostic testing would not be of benefit.

III. Default Management.

Observation and reassurance for mild reactions, as this will be the most likely encountered scenario.

A. Immediate management.

Pre-treatments

Pre-treatment can reduce incidence of reactions and regimens depend on timing of study:

If a patient with prior allergy needs an emergent study, treatment with methylprednisolone 100 milligram (mg) intravenously (IV) and diphenhydramine 50mg IV at least 1-2 hours prior to imaging can be used.

If non-emergent studies are planned for a patient with prior allergy, then the following regimen can be used (Greenberger protocol):

Prednisone 50mg orally with first dose given 13 hrs prior to administration of contrast.

A second dose of prednisone 50mg orally 7 hours prior to contrast.

A third, and last, dose of prednisone 50mg orally one hour prior to contrast.

Diphenhydramine 25-50mg IV given 1-2 hours prior to study can be used in conjunction.

Reactions

Mild reactions

If a patient with no prior allergy develops a mild reaction, in most cases treatment is not needed as reactions tend to be self-limited. Patients should be observed to ensure resolution of symptoms.

If a patient with a prior allergy states they often have a delayed mild reaction (up to 1 hour to 7 days later), they can be treated with tapering oral methylprednisolone as outpatient and sent home with careful discharge instructions.

Epinephrine 0.01milligram/kilogram (mg/kg) of body weight to a maximum of 0.5mg of 1:1000 concentrated epinephrine injected intramuscularly in the lateral aspect of the thigh (supplied usually in a 1ml glass ampule)

Other severe reactions

If bradycardia: atropine 0.6-1.0mg IV (and may repeat atropine times one for total adult dose of 2mg)

If seizures: diazepam 5mg IV

If severe hypertension: sublingual nitroglycerin as needed

If impending cardiac arrest: follow current basic cardiac life support (BCLS) protocols and activate code team

Extravasation

Apply warm compress, elevate extremity; notify surgical specialist if any of the following occur over the next 1-2 hours: progressive swelling, decreased capillary refill, blistering, change in sensation or increased pain.

D. Long-term management.

Skin testing is an option to find safe contrast mediums to use in patients with history of reaction, although not necessary given the more routine use of low osmolality and non-ionic contrast media.

More realistically, those with concerning moderate-to-severe reactions should consider alternative modes of imaging (or non-contrasted studies) if future testing needed.

E. Common Pitfalls and Side-Effects of Management

Those with seafood or iodine allergy need to be questioned more clearly about their reaction, as often this is not an absolute contraindication to contrast media. The risk of reaction in patients with seafood allergy is very similar to those with other food allergies or asthma. Allergies to shellfish in particular do not increase the risk of reaction, as often the reaction to shellfish is related to a muscle protein and not iodine. Patients with sensitivity to topical iodine solutions like Betadine are also not at an increased risk.

IV. Management with Co-Morbidities

A history of prior reactions, asthma and hay fever increase the risk of reactions by 1.5 up to 6 fold as compared to the general population. Thus a brief history and examination including vital signs should be obtained before contrast administered.

Those with history of reactions should be observed for at least 30 minutes after contrast exposure.

See section IIIA above regarding pre-treatment regimens.

A. Pregnancy and Breast-Feeding.

Low-osmolality iodinated contrast agents should be used with caution in pregnant patients. No mutagenic or teratogenic effects have been documented in animal studies with low-osmolality contrast media, but there are no well-controlled studies to verify this in humans. Based on current data regarding fetal thyroid function from water-soluble iodinated contrast agents, administration of these contrast agents during pregnancy does not require any additional management beyond routine medical care for the fetus, but long-term outcomes remain unknown. Routine pre-test pregnancy screening is not required prior to contrast media use.

Gadolinium-based contrast agents should avoid whenever possible in pregnant patients. They should only be used if their use is considered critical to patient care and other alternatives are not available. This decision should be made with close consultation with a radiologist and proper documentation.

The data is limited regarding safety in breast-feeding for both iodinated and gadolinium based contrast media. Based on the 2 hour half-life of most contrast media and the near complete clearance after 24 hours it is presumed to be safe to resume breast-feeding after this 24 hour period.

B. Renal Insufficiency.

Contrast-induced nephropathy is a multifactorial event (see section IIA above) leading to acute, oliguric renal failure and will not be discussed here, as it is not an "allergy" to contrast. Those with underlying or pre-existing renal disease or on nephrotoxic medications are at the highest risk for this complication.

Patients with underlying kidney disease should not receive gadolinium containing contrast agents due to their association with nephrogenic systemic fibrosis.

F. Diabetes or other Endocrine issues

Those patients taking metformin are advised to not resume that medication until 48 hours post contrast exposure due to a rare, but potentially life-threatening, risk of lactic acidosis after contrast exposure. The risk of lactic acidosis is primarily related to the degree of renal impairment not an interaction between metformin and the contrast media. Thus if a patient is in need of urgent imaging with iodinated contrast, or gadolinium in a usual dose range, and is not in acute kidney injury, stage IV or stage V chronic kidney disease, or has a procedurally related increased risk of kidney injury no extra precautions are explicitly necessary to protect renal function pre- or post-procedure.

G. Malignancy

None

H. Immunosuppression (HIV, chronic steroids, etc.).

None

I. Primary Lung Disease (COPD, Asthma, ILD)

Those with asthma or bronchospasm have higher incidence of reactions and may either need pretreatment or closer observation. This will depend on their medical history (lung disease and contrast reaction history), exam, type and dose of contrast used as well as your institutional radiologic protocols.

J. Gastrointestinal or Nutrition Issues

Those at risk of extravasation of enteric contrast should receive water soluble contrast. See Section IIA above.

K. Hematologic or Coagulation Issues

Those with multiple myeloma have higher incidence of contrast-induced nephropathy.

L. Dementia or Psychiatric Illness/Treatment

None; although if histamine type 1 (H1) blocker given, do note that it can cause agitation and/or confusion in the elderly.

Those with anxiety or apprehension may have higher incidence of mild reaction symptoms.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

Patients with prior allergy have an approximate 7-17% higher incidence of contrast-related reactions. See section IIIA for pretreatment regimens. Those with moderate-to-severe reactions should be evaluated for alternative forms of imaging (non-contrast or different modality).

B. Anticipated Length of Stay.

If a patient develops a moderate reaction that requires intravenous therapy, consider longer observation for delayed reaction and/or admission to hospital if concerning comorbidities (such as chronic lung disease). If a patient develops severe reaction, admission to hospital for monitoring may be warranted.

C. When is the Patient Ready for Discharge.

Discharge can be pursued when symptoms of reactions have reversed and no longer require frequent monitoring or intravenous therapy.

D. Arranging for Clinic Follow-up

Mild reactions tend to be self-limited and require no follow-up. Those with concerning moderate-to-severe reactions may require post-discharge follow-up depending on their complications and response to therapy.

1. When should clinic follow up be arranged and with whom.

Those with severe complications may require cardiovascular or pulmonary follow-up depending on their type of reaction and ensuing complications.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

None

E. Placement Considerations.

NA

F. Prognosis and Patient Counseling.

A prior history of reactions increases the risk of reoccurrence but does not increase the severity of reactions. See section IIIA for pretreatment regimens.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

NA

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

See section IIIA for pre-treatment regimens. Those with moderate-to-severe reactions should also be considered for alternative forms of imaging (non-contrast or different modality).

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